Colorectal carcinoma is a malignant neoplastic disease. There is a high incidence of colorectal carcinoma in the Western world. Tumours of this type often metastasize through lymphatic and vascular channels. Many patients with colorectal carcinoma eventually die from this disease. To date, systemic therapies and chemotherapies have been developed for the treatment of colorectal cancer. However, no therapies have exhibited sufficient anti-tumour activity to prolong the survival of colorectal carcinoma patients with metastatic disease with any degree of reliability. As a result, a need still exists to develop methods for the successful treatment or prevention of colorectal carcinoma.
In an article by Al-Azzawi et al. (“Estrogen and colon cancer: current issues”, Climacteric 2002; 5:3-14) current epidemiological data on the incidence and mortality of colon cancer in post-menopausal women using hormone replacement therapy is reviewed. Hormone replacement therapy (HRT) comprises the administration of estrogen to prevent or treat symptoms resulting from estrogen deficiency (hypoestrogenism). The authors conclude that estrogen use confers overall protection, with a reduction in the incidence of colon adenoma and carcinoma of about 30%. It is said that estrogen use reduces the colon cancer-related mortality.
U.S. Pat. No. 6,291,456 (Signal Pharmaceuticals Inc.) relates to compounds that modulate gene expression through the estrogen receptor as well as to methods for treating a large number of estrogen-related conditions, including colon cancer. The compounds according to this US-patent include both estrogen antagonists and agonists. It is observed in the patent that those compounds that are estrogen antagonists are useful as antiestrogens in, for example, breast and ovarian tissue and thus are useful in the treatment and prevention of breast and ovarian cancer. Those compounds that are estrogen agonists are recommended for other therapeutic and prophylactic uses.
As will be evident from the above publications, it has been suggested in the prior art that the administration of estrogens to postmenopausal females may help to reduce the risk of colon cancer. However, this observation does not automatically warrant the conclusion that it would be advisable to treat or prevent estrogen-suppressed cancers, such as colon cancer, by administering estrogen. Indeed, it is well known that estrogens increase the risk of “estrogen-stimulated cancers”, e.g. endometrial cancer in females (Cushing et al., 1998. Obstet. Gynecol. 91, 35-39; Tavani et al., 1999. Drugs Aging, 14, 347-357) and breast cancer in both females and males (Tavani et al., 1999. Drugs Aging, 14, 347-357; Pike et al., 2000. Steroids, 65, 659-664, Heinig et al. 2002, European Journal of Obstetrics & Gynecology, 102, 67-73), by inducing an estrogen receptor mediated increase in the frequency of cell division (proliferation) within these tissues. Cell division is essential in the complex process of genesis of human cancer since it per se increases the risk of genetic error, particularly genetic errors such as inactivation of tumour suppressor genes.
Since the incidence of the aforementioned estrogen-stimulated cancers in industrialised countries is very high, the administration of estrogens in the treatment or prevention of e.g. colon cancer is associated with very significant drawbacks. Thus, there is a requirement for an estrogen that could be employed in the treatment of estrogen-suppressed tumours without enhancing the risk of estrogen-stimulated tumours.
Prostate cancer is the second leading cause of cancer mortality in men in the USA. For the past six decades, hormonal therapy has been an important treatment of advanced prostate cancer. One such method employs diethylstilbestrol (DES) to suppress endogenous androgen production. DES is a substance that is known to exhibit estrogenic activity. However, the use of DES is marred by significant cardiovascular toxicity. Strategies to reduce thromboembolic events, such as dose reduction or the use of warfarin sodium were unsuccessful (Malkwicz et al., “The role of diethylstilbestrol in the treatment of prostate cancer”, Urology 2001 August; 58(2 Suppl 1):108-13). In addition, the application of DES is believed to enhance the risk of breast cancer.
Consequently, there is a need for an estrogenic substance that may be used in the treatment or prevention of estrogen-suppressed tumours, such as colorectal tumours or prostate tumours, and which does not impose a risk factor for the development of estrogen-stimulated cancers or display significant cardiovascular toxicity.